Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_033360.4(KRAS):c.194G>T (p.Ser65Ile)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA384152083

438796 (ClinVar)

Gene: KRAS

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 11365dcc-39b9-4e9d-9aa1-a14271cf89f0

Approved on: 2020-05-18

Published on: 2020-05-21

HGVS expressions

NM_033360.4:c.194G>T

NM_033360.4(KRAS):c.194G>T (p.Ser65Ile)

NC_000012.12:g.25227330C>A

CM000674.2:g.25227330C>A

NC_000012.11:g.25380264C>A

CM000674.1:g.25380264C>A

NC_000012.10:g.25271531C>A

NG_007524.1:g.28591G>T

NG_007524.2:g.28674G>T

NM_004985.4:c.194G>T

NM_033360.3:c.194G>T

NM_001369786.1:c.194G>T

NM_001369787.1:c.194G>T

NM_004985.5:c.194G>T

ENST00000256078.8:c.194G>T

ENST00000311936.7:c.194G>T

ENST00000557334.5:c.112-17419G>T

Likely Pathogenic

PS2 PP2 PM2 PS4_Supporting

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.194G>T (p.Ser65Ile) variant in KRAS was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 2 probands with clinical features of a RASopathy (PS4_Supporting; SCV000599968.1, PMID: 26822237, 25326635, Invitae internal data). The variant arose de novo in one of the probands with confirmed parentage (PS2; SCV000599968.1, PMID:26822237, 25326635). The variant is located in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581):, PS2, PS4_Supporting, PM2, PP2.

PS2

SCV000599968.1

PP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

Absent from gnomAD

PS4_Supporting

Seen once, de novo, in 9yo female with delayed motor milestones, delayed speech, developmental regression, hypotonia, hypertelorism, short stature, macrocephaly, joint contractures at elbows and hips, failure to thrive, ptosis, pulmonary stenosis, pelvic osteopenia, mild scoliosis and plexiform neurofibroma.(SCV000599968.1) Invitae: One juvenile male with congenital pulmonary valve stenosis, macrocephaly, gross motor delay

Curation History

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